1. The Third DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: ischemic postconditioning during primary PCI Thomas Engstrøm, MD, DMSci, PhD DANAMI3-iPOST

2. Disclosures The presenter has no disclosures with regard to the trial

3. DANAMI3-iPOST Rigshospitalet University Hospital Henning Kelbæk Steffen Helqvist Lars Køber Dan Eik Høfsten Lene Kløvgaard Lene Holmvang Erik Jørgensen Kari Saunamäki Frants Pedersen Peter Clemmensen Thomas Engstrøm Niels Vejlstrup Jacob Lønborg Kiril Ahtarovski Marek Treiman Klaus Fuglsang Kofoed Participating sites and investigators ClinicalTrials.gov n o NCT01960933 Aalborg University Hospital Hans-Henrik Tilsted Jan Ravkilde Svend Eggert Jensen Anton Boel Villadsen Jens Aarøe Bent Raungaard Christian Torp-Pedersen Data Safety and Monitoring Board (DSMB) Gorm Bøje Jensen Gunnar Gislasson David Erlinge Clinical Event Comité (CEC) Kristian Thygesen Anders Galløe Jørgen Jeppesen Skejby University Hospital Hans Erik Bøtker Anne Kaltoft Michael Maeng Lars R Krusell Christian J Terkelksen Odense University Hospital Lisette Okkels Jensen Karsten T Veien Funding The Danish Agency for Science, Technology and Innovation and Danish Council for Strategic research

4. Mortality in STEMI Jiménez-Candil et al., Rev Esp Cardiol 2013 DANAMI3-iPOST

5. Reperfusion injury Ischemia Garcia -Dorado et al., Cardiovasc Res, 2006 Cell death Time IschemiaReperfusion injury Ischemic injury

6. Normoxic heart DANAMI3-iPOST

7. Ischemia 90 minutes DANAMI3-iPOST

8. One minute reperfusion DANAMI3-iPOST

9. Conventional treatment coronary artery ReperfusionOccluded Reperfusion injury Reperfusion injury Ischemic postconditioning 30 30 sec30 Balloon inflations – deflations Ischemic postconditioning DANAMI3-iPOST

10. Ischemic postcondioning in STEMI – surrogate marker trials Heusch G, Lancet 2013

11. 1243 Randomized 617 Conventional primary PCI617 Ischemic postconditioning Trial flow chart 614received the allocated intervention 3 CABG 592received the allocated intervention 6 CABG 19 PCI failed or not feasible 617 analysed by intention to treat 3 lost to follow up after 12, 17 and 36 months 617 analysed by intention to treat 2 lost to follow up after 14 and 33 months DANAMI3-iPOST

12. 1243 Randomized 617 Conventional primary PCI617 Ischemic postconditioning Trial flow chart 614received the allocated intervention 3 CABG 592received the allocated intervention 6 CABG 19 PCI failed or not feasible 617 analysed by intention to treat 3 lost to follow up after 12, 17 and 36 months 617 analysed by intention to treat 2 lost to follow up after 14 and 33 months DANAMI3-iPOST

13. 1243 Randomized 617 Conventional primary PCI617 Ischemic postconditioning Trial flow chart 614received the allocated intervention 3 CABG 592received the allocated intervention 6 CABG 19 PCI failed or not feasible 617 analysed by intention to treat 3 lost to follow up after 12, 17 and 36 months 617 analysed by intention to treat 2 lost to follow up after 14 and 33 months DANAMI3-iPOST

14. 1243 Randomized 617 Conventional primary PCI617 Ischemic postconditioning Trial flow chart 614received the allocated intervention 3 CABG 592received the allocated intervention 6 CABG 19 PCI failed or not feasible 617 analysed by intention to treat 3 lost to follow up after 12, 17 and 36 months 617 analysed by intention to treat 2 lost to follow up after 14 and 33 months DANAMI3-iPOST

15. Inclusion criteria ST-segment elevation myocardial infarction Symptom duration of no more than 12 hours TIMI 0-1 in infarct related artery DANAMI3-iPOST

16. Exclusion criteria Unconsciousness or cardiogenic shock Stent thrombosis Indication for acute bypass surgery DANAMI3-iPOST

17. Power calculation One year all-cause mortality or hospitalization for heart failure was estimated to be 11% in the conventional PCI assignment group. A relative reduction in the primary endpoint of 25% can be detected with a two- sided alpha level of 0∙05 and a power of 80% by enrolling 1100 patients if all patients were followed for at least 2 years. DANAMI3-iPOST

18. Primary endpoint Composite All-cause mortality Hospitalization for heart failure Assessed when the last included patient had been followed for 2 years DANAMI3-iPOST

19. Baseline characteristics Conventional (n = 617) iPOST (n = 617) Median age (range, years)62 (29-94)63 (35-92) Men486 (79%)489 (79%) Women131 (21%)128 (21%) Diabetes50 (8%)55 (9%) Hypertension209 (34%)241 (39%) Current smoking306 (50%)294 (48%) Previous smoking171 (28%)170 (28%) Hyperlipidemia 181 (28%)173 (28%) Previous MI 36 (6%)30 (5%) Infarct location Anterior249 (40%)262 (43%) Inferior327 (53%)311 (50%) Posterior39 (6%)42 (7%) DANAMI3-iPOST

20. Conventional (n = 617) iPOST (n = 617) P No. of arteries treated per patient (n)1 (0-3) >0.05 Number of implanted stents (n)1 (1-2) >0.05 Stent diameter (mm)3∙5 (3∙0-3∙75) >0.05 Total stent length (mm)23 (17-33)23 (18-31) >0.05 Stent type >0.05 No stenting26 (4%)23 (4%) >0.05 Bare-metal20 (3%)18 (3%) >0.05 Drug-eluting571 (93%)576 (93%) >0.05 Pre-treatment with heparin590 (96%)596 (97%) >0.05 Use of Glycoprotein IIb/IIIa inhibitor67 (11%)89 (14%) >0.05 Use of Bivalirudin501 (81%)505 (82%) >0.05 Thrombus aspiration423 (69%)291 (47%) <0.001 Time from symptom onset to PCI (hrs)2∙9 (2∙0-4∙7)2∙9 (2∙1-4∙6) >0.05 Procedural data DANAMI3-iPOST

21. Conventional (n = 617) iPOST (n = 617) P Killip Class II - IV at any time49 (8%)33 (5%) >0.05 Multi vessel disease248 (40%)249 (40%) >0.05 Culprit lesion >0.05 LAD229 (37%)245 (40%) >0.05 RCA266 (43%)260 (42%) >0.05 CX59 (10%)52 (8%) >0.05 Other (D, OM, PLA, PDA)62 (10%)58 (9%) >0.05 Indeterminable1 (0∙2%)2 (0∙3%) >0.05 TIMI3 post procedure582 (94%)588 (95%) >0.05 Clinical characteristics DANAMI3-iPOST

22. Conventional (n = 617) iPOST (n = 617) P Antiplatelet therapy Aspirin − (%)601 (97%)605 (98%)>0.05 Clopidogrel − (%)99 (16%)92 (15%)>0.05 Prasugrel − (%)264 (43%)269 (44%)>0.05 Ticagrelor − (%)245 (40%)249 (40%)>0.05 Statin − (%)602 (98%)597 (97%)>0.05 Betablocker − (%)544 (88%)549 (89%)>0.05 ACE inhibitor or angiotensin-II-receptor blocker − (%)286 (46%)323 (52%)>0.05 Calcium channel blocker − (%)46 (8%)55 (9%)>0.05 Medical theraphy at discharge DANAMI3-iPOST

23. Primary endpoint – median follow up 37.5 months DANAMI3-iPOST

24. All cause mortality – median follow up 37.5 months DANAMI3-iPOST

25. Heart failure – median follow up 37.5 months DANAMI3-iPOST

26. Outcome Conventional (n = 617) iPOST (n = 617) Hazard ratio [95% CI]p Primary composite endpoint69 (11∙2)65 (10∙5)0·93 [0∙66 – 1∙30]0∙66 All-cause mortality50 (8∙1)38 (6∙2)0∙75 [0∙49 – 1∙14]0∙18 Heart failure hospitalization30 (4∙9) 0∙99 [0∙60 – 1∙64]0∙96 Cardiovascular mortality30 (4∙9)26 (4∙2)0∙86 [0∙51 – 1∙45]0∙56 Recurrent myocardial infarction29 (4∙7)33 (5∙4)1∙13 [0∙68 – 1∙86]0∙64 TVR by PCI14 (2∙3)19 (3∙1)1∙35 [0∙67 – 2∙68]0∙40 TVR by CABG2 (0∙3)6 (1∙0)2∙97 [0∙60 – 14∙72]0∙28 DANAMI3-iPOST outcomes DANAMI3-iPOST

27. Conventional (n = 299) iPOST (n = 275) P LVEF all patients (%)50.852.7 <0.05 LVEF anterior infarcts (%)45.949.5 0.04 Number of patients with LVEF >45%215 (72%)220 (80%) 0.015 DANAMI3-iPOST DANAMI3-iPOST outcomes

28. Subgroup analysis DANAMI3-iPOST

29. Conclusions Ischemic postconditioning during primary angioplasty in STEMI patients failed to reduce the rate of the primary composite endpoint of all-cause mortality and hospitalization for heart failure. Ischemic postconditioning reduced the secondary endpoint of all cause mortality by 25% but this reduction did not reach statistical significance. Ischemic postconditioning significantly increased the number of patients with left ventricular ejection fraction above 45% after 18 months. DANAMI3-iPOST